What Is the Natural History and Likelihood of Progression of Indeterminate Pulmonary Nodules in Patients With Extremity Osteosarcoma?

Background Indeterminate pulmonary nodules are frequently identified on staging chest CT scans in patients with extremity osteosarcoma; however, their malignant potential and prognostic implications remain unclear. Understanding the natural history of indeterminate pulmonary nodules and the prognostic value of individual nodule characteristics is important to help guide surveillance and management decisions. Questions/purposes (1) What proportion of indeterminate pulmonary nodules progress to overt pulmonary metastasis, and what is the median time to progression? (2) Are specific radiographic characteristics—such as size, number, laterality, and calcification—associated with nodule progression or survival? (3) Do patients with indeterminate pulmonary nodules at diagnosis have inferior overall survival compared with patients without pulmonary nodules? Methods We retrospectively reviewed 202 pediatric and adult patients with extremity osteosarcoma treated at a single institution between January 2016 and December 2022, with follow-up until June 2024. At initial presentation, we created three distinct study groups based on baseline high-resolution chest CT findings (0.625-mm slice thickness): group 1, those with indeterminate pulmonary nodules (patients presenting with any number of pulmonary nodules measuring < 10 mm [n = 40]); group 2, those without pulmonary nodules (patients with no detectable lung nodules [n = 146]); and group 3, those with metastasis (patients with pulmonary nodule(s) measuring ≥ 10 mm [n = 16]). Of the 40 patients with indeterminate pulmonary nodules, 58% (23 of 40) were male and 43% (17 of 40) were female, with a median (range) age at presentation of 16 years (7 to 53) High-resolution CT chest images of the indeterminate pulmonary nodule group were independently reviewed by a blinded radiologist, characterizing nodules by size (≤ 5 mm versus 6 to 10 mm), number, distribution, laterality, and calcification. Longitudinal nodule behavior was classified as progressive, regressive, or static. Progression was defined as an increase in size ≥ 1 mm or in number by ≥ 1; while regression was defined as a decrease in size ≥ 1 mm or in number by ≥ 1, with remaining nodules stable. Confirmed pulmonary metastases were defined specifically as any initial baseline indeterminate pulmonary nodule that demonstrated growth to a maximum diameter of > 10 mm during the longitudinal follow-up period. Chest CT scans were done before surgery and at completion of therapy. Thereafter, chest CT scans were performed every 3 months for the first 3 years, every 6 months between years 3 and 5, and annually after the fifth year. Survival outcomes were analyzed using Kaplan-Meier methods, and the association of nodule characteristics with survival was assessed with Cox proportional hazards regression. Results Overall, 58% (23 of 40) of indeterminate pulmonary nodules progressed across the follow-up period, with 25% (10 of 40) of patients developing confirmed pulmonary metastasis; the median (range) time to nodule progression was 19 months (3 to 22). No individual nodule characteristic—including size, number, laterality, or calcification—was associated with progression or survival on multivariate Cox regression analysis. Patients with indeterminate pulmonary nodules had worse 2-year overall survival than patients without metastasis (55% [95% confidence interval (CI) 40% to 71%] versus 76% [95% CI 70% to 83%]; p < 0.001). The median overall survival for patients with indeterminate pulmonary nodules was 27 months (95% CI 19 to 36). Conclusion Our study showed an association with indeterminate pulmonary nodules and survival and suggests that patients who present with indeterminate pulmonary nodules have worse overall survival than those who do not. No individual nodule characteristic was associated with disease progression in our cohort, but we cannot exclude the possibility that with more numbers, an association might be present. Our study suggests that vigilant surveillance is warranted for patients with indeterminate pulmonary nodules until prospective studies with more patients are conducted to better develop evidence-based management and surveillance protocols. Level of Evidence Level III, prognostic study.